Parkinson's disease (PD) is characterized by progressive neuronal loss in multiple brain regions. Particularly affected is the substantia nigra pars compacta (SNpc) of the midbrain. In PD, this region shows degeneration of dopaminergic neurons and deficient mitochondrial respiratory chain complex I activity. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a complex I inhibitor, has caused human parkinsonism by selectively killing SNpc dopaminergic neurons. Several pesticides, including rotenone, also selectively inhibit complex I and cause SNpc dopaminergic neurodegeneration in animal models. Human epidemiological studies have now linked pesticide exposure to an increased risk for PD. One recent study implicated occupational exposure to rotenone. It is therefore plausible that environmental toxicant (pesticide) exposure causes the complex I deficiency seen in PD, and that this mechanism is central to disease initiation and/or progression. Our research goal is to identify natural protective strategies employed by the brain against neurodegeneration induced by complex I-inhibiting environmental toxicants. Ultimately, we hope to exploit these mechanisms to develop novel disease-modifying therapies against PD. Our recent work has identified DJ-1 over-expression in astrocytes as a neuroprotective mechanism against complex I-inhibiting pesticides in vitro. This process appears to involve astrocyte-released factors, and may be particularly relevant to PD because (i) reactive astrocytes over-express DJ-1 in sporadic PD and (ii) mutations that eliminate DJ-1 expression cause familial PD. Thus, we hypothesize that astrocytic DJ-1 over-expression in the human brain may represent a natural neuroprotective attempt against PD. If true, this process may be targetable for augmentation as disease-modifying therapy. To model this possibility in the intact brain, we will assess the capacity of astrocytic DJ-1 over-expression to reduce MPTP-induced SNpc dopaminergic neurodegeneration in transgenic mice (Aim 1). This will be studied using behavioral, immunohistochemical, and biochemical analyses in novel mice, recently developed in our lab, that over- express DJ-1 selectively in astrocytes under control of the glial fibrillary acidic protein promoter. We will also assess the capacity of lentivirus-mediated astrocytic DJ-1 over-expression to perform similarly against rotenone in rats (Aim 2). In each case, we hypothesize that astrocytic DJ-1 over-expression will augment astrocyte-mediated neuroprotection against complex I inhibition. Aim 2 will also test an experimental translational gene therapy approach against pesticide-induced neurodegeneration. In our final Aim we will use analytical chemistry methods to identify the DJ-1-modulated, astrocyte-released soluble factor(s) that carry the neuroprotective activity in our cell culture model. These factors, or the mechanisms they employ, may also generate novel therapeutic strategies against pesticide-induced neurodegeneration and PD. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) is a common neurodegenerative disorder for which we still have no cure or disease-modifying therapies. Environmental pesticide exposure may be a risk factor for, or a cause of, PD. This research project aims to identify DJ-1-dependent, astrocyte-centered mechanisms that may be therapeutically targetable against environmental toxicant (pesticide)-induced PD.